The Program Project is designed to use modern genetic approaches in the study of key components and events in the development, function, and repair of the vertebrate central nervous system. Major areas of molecular neuroscience to be studied include cell-cell interactions (Project 1), signaling via intracellular second messenger systems (Project 2), and genes that contribute to nervous system pattern formation (Project 3). The approaches to be used include creation of animals with specific germ line mutations by homologous recombination in embryonic stem cells, analysis of the fate of individual mutant precursor cells in a normal tissue environment, and identification of specific disease genes by newly devised methods utilizing the mapping of overlapping deletions. This program requires a synergistic and innovative application of the expertise represented by several investigators, with integration of this expertise at both the technical and interpretive stages of each project. Integration is facilitated through three Cores: Administrative, Gene Targeting, and Phenotypic Analysis, that are utilized by each project and provide for unusual economy of effort and expense in this type of research . The combination of results obtained in analysis of the different systems described will provide for a more comprehensive understanding of molecular systems at the tissue level in the intact animal. This body of fundamental information on the assembly and function of the central nervous system is of direct relevance to human health problems concerning defects in brain development and the resulting dysfunction and mental retardation.